18 Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Palbociclib in ER-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Advanced Breast Cancer: Phase 1b Cohort

18 Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Palbociclib in ER-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Advanced Breast Cancer: Phase 1b Cohort

Background

Vepdegestrant (ARV-471) is an oral proteolysis-targeting chimeras (PROTAC) estrogen receptor (ER) degrader. In a phase 1/2 study (NCT04072952), vepdegestrant monotherapy had a favorable safety profile and encouraging clinical activity with robust ER degradation. The phase 1b cohort of this study is evaluating vepdegestrant plus the CDK4/6
inhibitor palbociclib.

Methods

Eligible patients had estrogen receptor-positive (ER+)/HER2-negative (HER2–) advanced breast cancer and had received 1 or more prior endocrine therapies and less than 2 chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor treatment was permitted. Vepdegestrant was given orally once daily continuously at doses of 180 mg (n = 2), 200 mg (n = 21), 400 mg (n = 3), or 500 mg (n = 20); palbociclib 125 mg was given orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. Primary end points were dose-limiting toxicities (DLTs) in the first cycle and safety.

Results

As of June 6, 2023, 46 patients were enrolled (female, 97.8%; median age, 62.0 years [range, 29-78]). Patients had received a median of 4 prior therapies (1-11) in any setting (CDK4/6 inhibitors, 87.0%; fulvestrant, 80.4%; chemotherapy, 76.1% [45.7% in metastatic setting]). There were no DLTs. Treatment-emergent adverse events (TEAEs) leading to dose reductions or discontinuation of vepdegestrant occurred in 5 and 4 patients, respectively. TEAEs leading to dose reductions or discontinuation of palbociclib occurred in 34 and 8 patients, respectively. Grade 3/4 treatment-related AEs (TRAEs) to either treatment in 10% of patients or more were neutropenia (89.1%), decreased white blood cell count (15.2%), and decreased platelet count (10.9%); no grade 5 TRAEs or febrile neutropenia occurred. The clinical benefit rate (rate of confirmed complete response, partial response, or stable disease at 24 weeks or more) with vepdegestrant plus palbociclib was 63.0% (95% CI, 47.5-76.8). Objective response rate in patients with measurable disease at baseline (n = 31) was 41.9% (95% CI, 24.5-60.9). Pharmacokinetics showed dose-dependent exposure for vepdegestrant; palbociclib exposure was similar across dose levels of vepdegestrant and modestly higher compared with historical data. Substantial, sustained decreases in mutant ESR1 circulating tumor DNA levels were observed.

Conclusion

Vepdegestrant plus palbociclib showed promising clinical activity in patients with heavily pretreated ER+/HER2– advanced breast cancer. The safety profile of vepdegestrant plus palbociclib was generally consistent with the known safety profiles except for increased grade 3/4 neutropenia (managed with monitoring and palbociclib dose reductions).